Evaluation of Haloperidol for Treatment of ICU Delirium

By: Nancy Yousry, PharmD Candidate c/o 2024

Delirium is characterized as impaired cognition with a wide range of manifestations that are nonspecific to the state, making it harder to detect in its earlier stages.¹ Inadequate management has frequently resulted from a failure to recognize the condition. Elderly patients are most often susceptible to delirium when checked into the intensive care unit (ICU). Some of the negative consequences of delirium in ICU patients include increased mechanical ventilation duration, prolonged hospitalization, increased rates of self-extubation, and increased risk of mortality.¹

ICU Delirium Diagnosis

ICU Delirium is typically seen in patients who have experienced prolonged intubation and usually presents as a disturbance of consciousness within short periods of time and distinct changes in psychotic features from baseline. According to the American Psychiatric Association, there are five available tools utilized for valid screening of delirium in adult patients. The two most commonly used studies in clinical practice are Confusion Assessment Method-ICU (CAM-ICU) and Intensive Care Delirium Screening Checklist (ICDSC).¹

Risk Factors for ICU Delirium

One study conducted in a medical ICU discovered several modifiable and non-modifiable risk factors that increase a geriatric patient’s susceptibility to ICU delirium. For example, hypertension-related vascular damage predisposes patients to cerebral hypoxia, increasing their risk of altered mental states and progression into delirium. Additionally, some of the modifiable risk factors associated with increased susceptibility to ICU delirium include the use of certain classes of medication, such as steroids, benzodiazepines, and morphine analgesics.²

An Overview of Haloperidol

Haloperidol, a first-generation antipsychotic drug, mechanistically works to block postsynaptic dopamine (D2) receptors in the mesolimbic system of the brain. In addition to this, haloperidol exhibits anti-noradrenergic, cholinergic, and histaminergic activity. Due to its nonselective nature, the blocking of these various receptors is associated with various adverse drug reactions. Such include extrapyramidal symptoms such as acute dystonia, akathisia and neuroleptic syndrome, while others can encompass anticholinergic effects such as elevated temperature, dry mouth or sedation. Assurance of appropriate dosing by the pharmacist is of importance to minimize toxicity and maximize therapeutic efficacy.³

Clinical Effects of Haloperidol in ICU Delirium Treatment

The New England Journal of Medicine reported a multicentered, blinded, placebo-controlled trial that randomly assigned adult patients with delirium admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered as needed for recurrences for as long as delirium continued. The primary outcome of this study was the number of days alive and out of the hospital at 90 days after randomization. From the 963 patients analyzed, it was revealed that the mean number of days alive and out of the hospital at 90 days was 35.8 in the haloperidol group and 32.9 in the placebo group [adjusted mean difference: 2.9 days; 95% confidence interval (CI) -1.2 to 7.0; p = 0.22]. Although  the difference between the two groups was not statistically significant, it shows promise that haloperidol may have potential as a treatment option. Meanwhile, the mortality rate at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference: -6.9; 95% CI -13.0 to -0.6), further supporting the use of haloperidol in ICU delirium.⁴

Nonpharmacologic Prevention

Due to the lack of conclusive data for haloperidol, it is recommended that nonpharmacologic strategies for minimization of risk factors be practiced as well. Such practices include early rehydration, establishing a sleep protocol, timely removal of catheters, and physical restraints.⁵

Conclusion

ICU delirium is a condition that is unavoidable in nature for some elderly patients with comorbidities that make them vulnerable to it. Further research is needed to conclude haloperidol’s efficacy in treating ICU delirium, and to assess the spectrum of side effects and their consequences on treatment progression.

References

1. Arumugam S, El-Menyar A, Al-Hassani A, Strandvik G, Asim M, Mekkodithal A, Mudali I, Al-Thani H. Delirium in the Intensive Care Unit. J Emerg Trauma Shock. 2017 Jan-Mar;10(1):37-46. doi: 10.4103/0974-2700.199520.
2. Tilouche N, Hassen MF, Ali HBS, Jaoued O, Gharbi R, El Atrous SS. Delirium in the Intensive Care Unit: Incidence, Risk Factors, and Impact on Outcome. Indian J Crit Care Med. 2018 Mar;22(3):144-149. doi: 10.4103/ijccm.IJCCM_244_17.
3. Rahman S, Marwaha R. Haloperidol. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2022. PMID: 32809727.
4. Andersen-Ranberg NC, Poulsen LM, Perner A, et al. Haloperidol for the treatment of delirium in ICU Patients. N Engl J Med. 2022;387(26):2425-2435. doi:10.1056/NEJMoa2211868
5. Management of delirium in the ICU. Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center. Accessed May 17, 2023. https://www.icudelirium.org/medical-professionals/delirium/management-of-delirium-in-the-icu.